Summary The ability to modify behavior based on environmental information and feedback is critical for survival. For example, a response that was once adaptive can become obsolete because of changes in environmental conditions. Similarly, a response that is appropriate in one environmental setting may be inappropriate, or even deadly, in another. Indeed, an essential aspect of adaptive behavior is to be able to recognize and use information about the current environmental setting, or context, to guide behavioral responding. In this way, contextual cues often indicate whether or not a particular response will result in a favorable outcome, and if not, that it should be inhibited. To date, a substantial amount of research has focused on the involvement of the prefrontal cortex (PFC) in response inhibition. At the same time, research from our laboratory and others has revealed that posterior cortical areas, such as retrosplenial cortex (RSC), are essential for encoding and retrieving contextual information. However, these two lines of research have proceeded relatively separately and it remains largely unknown if and how PFC and RSC interact to support the use of contextual information to guide behavior. To address this, the proposed experiments will test the hypothesis that RSC provides contextual information directly to the PFC and that this information is essential for effective response inhibition. This proposal addresses unanswered questions about the specific anatomical connections between the RSC and PFC, as well as the function of these connections (Specific Aim 1). Behavioral inhibition is known to rely upon PFC function, but how input from the RSC contributes to specific inhibitory mechanisms is unknown. In Specific Aims 2 and 3 an innovative technique, DREADDS, will be used to temporarily inactivate neurons that project specifically from the RSC to the PFC (Aim 2) or from the PFC to the RSC (Aim 3) in order to isolate the role of this circuit in two types of inhibitory behavior. In sum, this proposal examines the role of RSC input to the PFC in inhibitory behavior, a process that is disrupted in several psychiatric illnesses, including ADHD and schizophrenia. Additionally, this proposal investigates sex differences in the functions of these circuits, an important detail given that many disorders are characterized as having sex differences in etiology and symptomology.